Pathophysiology, Diagnosis and Management of Hyponatremia

OBJECTIVES:

Mechanisms that regulate sodium and water

Management of acute symptomatic hyponatremia

Patients at risk of osmotic demyelination syndrome and how to prevent it

This post reviews more in depth the pathophysiology and management of hyponatremia. The website itself serves as the teaching platform or as a learning resource. For a quick and easy diagnostic approach to hyponatremia, please see our 3 Lab Approach to Diagnosis.

Pathophysiology Review:

Serum Na concentration is determined by the relationship between the body’s extracellular osmotically active solutes (Na and K) and total body water.

Naserum = [Na + K]
Total body water

Decreases in solute (Na and/or K) intake or excess of total body water will result in fall in serum sodium level.

Antidiuretic hormone (or ADH) is the primary regulator of total body water and plasma osmolarity. In states of severe volume depletion and hypotonicity/hypo-osmolarity, volume status overrides low plasma osmolarity to drive ADH secretion2.

Diagnostic Work-up and Management:

In acute hyponatremia, altered mentation occurs because of cerebral edema (extracellular water enters brain cells by osmosis because the cells have not had time to adapt). This requires emergent therapy to rapidly increase serum Na.

Because assessment of volume status is often challenging and unreliable, the evaluation of hyponatremia can be broken down into “ADH on” and “ADH off” disorders. A small volume challenge of 0.5 L isotonic fluid can be given to aid in the diagnosis of hypovolemic hyponatremia2,6.

In chronic hyponatremia, neurons have adapted by creating idiopathic osmoles. Abrupt changes in extracellular osmolarity (with rapid rise in serum Na) causes water to exit cells into the extracellular space, resulting in cell death and demyelination.

Patients with hypokalemia, alcoholism, malnutrition, or liver disease have the highest risk for osmotic demyelination syndrome (ODS)6. The US guidelines recommend an upper limit of correction of 8 mEq/L per day in high risk patients to avoid precipitating ODS. Some authors have proposed even stricter correction guidelines of 4-6 mEq/L per day6. The symptoms of this syndrome presents > 48 h after overcorrection.

Patients with initial Na < 120 and arguably anyone with profound hyponatremia (Na < 125) should have their Na relowered with hypotonic fluids or dDAVP if they overcorrect6.

Patients at highest risk of overcorrection are those taking thiazides or those with volume depletion or adrenal insufficiency1. Once the stimulus for ADH secretion is removed with volume repletion, steroid replacement or stopping the offending agent, a water diuresis occurs.

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CT Interpretation

There is basilar predominant fibrosis without honeycombing with subpleural sparing in the posterior lung bases (fibrosis spares the area just adjacent to the pleura). This pattern is consistent with NSIP (nonspecific interstitial pneumonia). NSIP (nonspecific interstitial pneumonia) is a histologic finding characterized by peripheral, peribronchovascular ground glass opacities with associated fibrosis. There is basilar predominance and subpleural sparing may be present.

Circled in green is the spleen which appears hyperdense.

Time to Radiographic Resolution

Risk Factors for Delayed Resolution

CT interpretation

CT additionally showed some small subcentimeter pulmonary nodules that are indeterminate.

Nonsurgical Options for Pseudocyst Drainage

In primary adrenal insuffiiciency, the insult is at the level of the adrenal glands so there is a decrease in both cortisol and aldosterone. It is the mineralocorticoid deficiency (aldosterone) that results in hypovolemia, which can result in profound shock.

HPA Axis Pathophysiology

ECG Interpretation

This rules out benign J point elevation as an explanation for the ST segment elevations seen on the first ECG.

Spontaneous bacterial peritonitis (SBP) occurs in up to 30% of patients with cirrhosis and ~ 10% of inpatients2. SBP occurs when enteric flora seeds and infects the ascitic fluid. Thus, the most common pathogens are enteric GNRs (E. coli, Klebsiella). This is in contrast to secondary bacterial peritonitis (from gut perforation or secondary seeding from another intraabdominal infection) which often causes polymicrobial or fungal peritonitis.

SBP can be subtle in presentation – essentially every patient admitted with cirrhosis and ascites should get a diagnostic paracentesis. SBP has a high in-hospital mortality of ~ 20%2. Early paracentesis within 12 hours of physician contact is associated with improved mortality. Each hour delay was associated with 3.3% increase in mortality1.

Presumptive SBP (ascitic PMNs > 250) is treated with a full course of IV antibiotics for 5 days. Albumin should be given to patients with advanced liver or renal failure (Cr > 1, BUN > 30, Tbili > 4), which has been shown to improve hospital mortality and ↓ risk of AKI2.

Prophylaxis should be given to patients with a history of SBP, active GI bleeding, and anyone with advanced liver or renal disease who would have a poor outcome with development of SBP.

Varices and GI bleeding

Varices are dilated vessels that shunt blood around high pressure portal system. Esophageal varices are the most common cause of upper GI bleeding (UGIB) in patients with cirrhosis. Other portal hypertensive causes of UGIB include gastric varices and portal hypertensive gastropathy (PHG).

Prevention: indicated in patients with moderate and large varices and small varices with severe liver disease

non-selective beta-blockers

Decreases portal pressures, target HR < 55

Should be discontinued in patients with refractory ascites, SBP or significant hypotension (SBP threshold of 90 or 100)1

Serial esophageal banding

TIPS

Theoretical Mechanism of Lactulose

Hepatic Encephalopathy

Hepatic encephalopathy (HE) occurs in at least 30-40% of patients with cirrhosis2. HE occurs because ↓ clearance of NH3 (produced by gut bacteria) by the liver → ↑ glutamine in brain cells → brain swelling.

HE is a clinical diagnosis and ranges from ↓ attention to coma. Patients may have asterixis, hyperreflexia and very rarely focal neurologic deficits. Ammonia level is not a routine part of our work-up and is not needed for diagnosis (correlates with severity to a degree)2. Work-up should focus around evaluation of potential triggers:

Use of polyethylene glycol (PEG) requires more study (small studies have shown non-inferiority to lactulose when 4L of PEG was given over 4 hours)4

AKI in Cirrhosis (HRS)

This provides a brief overview of AKI in cirrhosis and hepatorenal syndrome (HRS). More detailed chalk talk can be found here. The vast majority of AKI in cirrhosis is pre-renal (>60%) and is induced by volume depletion (overdiuresis), GI bleeding, sepsis or hepatorenal syndrome. The other component is largely made up of intrarenal causes (>30%) such as ATN. Work-up should include routine work-up for AKI such as urinalysis and urine lytes. Since SBP is a common precipitant of both prerenal AKI and HRS, a diagnostic paracentesis should be performed in all patients. An albumin challenge helps differentiate between HRS and other pre-renal causes of AKI.

Liver transplant is definitive therapy, dialysis is often used as a bridge to transplant

Ascites

Ascites is the most common complication of cirrhosis (and most patients with ascites have ascites because of liver disease). The evaluation of patients with new ascites should include a diagnostic paracentesis to evaluate for ascites albumin, ascites fluid total protein and serum albumin.

New or worsening ascites from portal hypertensive causes should additionally prompt work-up with a RUQ US with duplex to rule out new portal system thrombosis.

Management:

Sodium restricted diet (except for Na < 120)

Diuretics – furosemide/spironolactone at a ratio of 20/50 respectively

Refractory ascites occurs when patients do not respond to maximal doses of diuretics or cannot tolerate ↑ diuresis without compromise in renal function. These patients can be managed with serial large volume paracenteses and/or TIPS (addresses underlying portal hypertension).

Overview of Cirrhosis

Set up the left side of your board as shown. The first part will discuss components of a “one-liner” or summary statement for patients with cirrhosis. You can give an example statement to help illustrate each part:

“60 M with decompensated alcoholic cirrhosis with a baseline MELD-Na of 23 complicated by a history of ascites and encephalopathy who presents with ___. “

Causes of cirrhosis – causes are listed in order of prevalence. Generally, the causes of cirrhosis do not significantly impact how we manage the complications of their disease

Compensated?

Compensated – no complications such as ascites, encephalopathy, variceal bleeding, hepatocellular carcinoma, etc. Patients are often asymptomatic for years and can leave for more than a decade.

Decompensated – poor median survival of < 2 yrs. Five year survival on the order of ~20%.

Anticoagulation is considered in group 1 and group 4 PH. Group 2 and 3 PH treatment is mostly directed at treating underlying disease. Advanced therapies vasodilate the pulmonary vasculature and are mostly for group 1 PH but occassionally are used in other groups.

CCB – most commonly amlodipine, diltiazem, nifedipine. Use is guided by response to vasoreactivity testing during RHC.

Anyone with suspected group 1 PH should receive RHC, which offers definitive diagnosis. Additionally able to measure/calculate PCWP pressure (↑ in group 2, low in other groups), PVR (> 3 Woods units in group 1 or PAH).

Groups of Pulmonary Hypertension

Move to section 2 of your board and fill in the table as your walk through each group of pulmonary hypertension. Pulmonary hypertension is divided into 5 general groups. To help remember them, we use the “number trick” – draw the group number and its reflection.

Miscellaneous – this group includes a mix of diseases that don’t clearly fit into other categories. Of note, there are frequently overlap with other groups (e.g., thyroid and metabolic disorders also can cause group 1 PAH)

Doxycycline – variable activity against MRSA that is institution/region dependent, poor Strep coverage. Has atypical coverage and is an alternative to azithromycin and FQs for patients with QTc prolongation.

Fluoroquinolones

Fluoroquinolones (FQs) are generally split into urinary and respiratory fluoroquinolones.

Urinary FQs: Levofloxacin and ciprofloxacin achieve good concentrations in the urine. Moxifloxacin does not concentrate in the urine and is thus ineffective at treating UTIs.

Ciprofloxacin – some MSSA coverage but poor Strep coverage, which is why it’s not used as a primary respiratory FQ.

Levofloxacin – adds Strep coverage

Respiratory FQ: Ciprofloxacin is excluded because of its poor Strep coverage, but does reach the lungs in adequate concentrations. It is sometimes used for double Pseudomonal coverage in CF patients.

Octreotide causes splanchnic vasoconstriction and can be dosed up 200 μg TID.

Vasopressors counteract systemic vasodilation. On the floor, we most commonly use midodrine, which can be dosed up to 15 mg TID. Our goal is to increase MAP by > 15 mmHg.

TIPS can be considered in patients without advanced cirrhosis.

Liver transplant is the only definitive treatment option. Dialysis can be used as a bridge to transplant.

Diagnosis and Definition of HRS

Draw the “Diagnosis,” “Definition,” and “Treatment” headers. Fill in the rest of the chart, moving left to right as you walk through each section.

Diagnosis: If you remember back, HRS can be differentiated from other causes of AKI because it is not volume responsive. For an adequate volume challenge, we give albumin 1 g/kg x 48 hr and stop all diuretics. If the Cr fails to improve after the albumin challenge, this is suggestive of HRS.

Definition: There are two types HRS.

Type 1 is severe, rapidly progressive and has high mortality (mean survival of ~ 2 weeks). It is defined by an ↑ in Cr > 2.5 within 2 weeks.

Type 2 is slowly progressive over weeks to months and often results in moderate renal insufficiency. Mean survival time is 4-6 months.

Pathophysiology in Decompensated Cirrhosis

Add “De” to the previously written “compensated” and add an additional downward arrow in front of the liver function to indicate worsening function. The numbering below corresponds to the diagram. Draw each section of the diagram as you work through the steps.

Worsening liver dysfunction results in loss of compensatory increase in cardiac output (for a variety of reasons that includes development of cirrhotic cardiomyopathy), which results in systemic hypotension and ↓ EAV

In compensated cirrhosis, the heart increases cardiac output (CO) to compensate so there is minimal change in EAV and plasma volume

Differential of AKI

Start by writing on a blank area of the board. AKI is common in patients with cirrhosis and occurs in ~ 20% of hospitalized patients. It sigificantly increases mortality so prompt evaluation is warranted.

Fill in the prevalences of pre-renal, renal and post-renal AKI as you mention them. Evaluation of AKI in ESLD should initially include a urinalysis to look for casts and a FeNa or FeUrea to differentiate between pre-renal, renal and post renal causes. The most common causes of AKI in ESLD are pre-renal (>60%). Obstructive AKI only makes up <1% of all causes of AKI so renal US may not be necessary in all patients.

Additionally, evaluation of AKI in cirrhosis should involve evaluation for infection (even in the absence of fever or leukocytosis), GI bleeding, and liver function.

Next, have your learners list causes of pre-renal and renal AKI, filling in the table as you go. Highlight that hypovolemia and sepsis result are volume responsive but HRS is not. Not listed on this diagram is cardiorenal cause of AKI, which would worsen with volume repletion.

Higher level learning point: Urine studies are not reliable at distinguishing ATN from HRS in patients with ESLD. Granular casts can be seen in severe hyperbilirubinemia and are not specific to ATN. FeNa may still be low in the setting of ATN in cirrhotics (see pathophysiology below)5.

A cyst has thin walls (< 2 mm) and may rarely contain fluid or solid material. A bulla is also thin walled (usually < 1mm, sometimes imperceptible) and is often accompanied by emphysema. Bulla also tend to be subpleural rather than within the lung parenchyma

ROS:– No for history volume depletion– No infectious symptoms (fevers, chills, localizing signs/ symptoms of infection)– No medication nonadherence or new medications except for doxcycyline and tacrolimus

Hyperkalemia Treatments

In patients with renal dysfunction, IV insulin 5 U is recommended over full 10 U with D50W.

Kayexelate, or sodium polystyrene sulfonate

Should not be given to patients with history of recent bowel surgery, ileus, or constipation as it can cause bowel necrosis

Auscultate for the systolic blood pressure. As you decrease the cuff pressure, take note of the pressure when you can first hear a Korotkoff sound (audible heartbeat). These sounds are initially only present on inspiration and disappear with expiration.. Continue to lower the cuff pressure until you can here Korotkoff sounds throughout the respiratory cycle. Pulsus paradoxus is defined as difference between these pressures of >10 mmHg. If the difference is >12 mmHg in a patient with a pericardial effusion, it is 98% sensitive and 83% specific for tamponade.

This patient had a pressure difference of 6 (no pulsus paradoxus). TTE confirmed no evidence of tamponade.

Of note, pulsus paradoxus is not a paradox at all. It is an exaggeration of the normal effects of the respiratory cycle on blood pressure. During inspiration, negative intrathoracic pressure increases venous return to the right heart. Increased right ventricular pressures result in mild bowing of the septum into the left ventricle and results in decrease in cardiac output and thus blood pressure. With cardiac tamponade, there is ventricular interdependence so septal bowing into the left ventricle during inspiration is more pronounced.

CT Chest Interpretation

Pseudohyponatremia and Hyperosmotic Hyponatremia

Artifact or pseudohpyonatremia (i.e. hypertriglyceridemia) – Most of our plasma is water plasma, but there is also a small percentage (around 7%) that is made up of lipids and proteins. What we really care about is the water plasma. However, our standard plasma [Na] lab measures the whole plasma. When there are a lot of lipids (i.e. hypertriglyceridemia) or lots of protein (i.e. multiple meyloma) this will dilute our measurement and give us a falsely low [Na], even though the [Na] in the water plasma is still normal. To verify that this is the case send a ‘whole blood’ [Na], which will just measure the water plasma.

Active Osm (i.e. Glucose) – compounds that do not freely cross the cell wall and osmotically pull water out of the cell, into the extracellular plasma in order to equilibrate the Osm gradient and consequently diluting the concentration of Na.

Inactive Osm (i.e. BUN and EtOH) – Freely cross the cell membrane and thus do not pull water into the extracellular plasma. However, these Osm are occasionally the consequence of a primary process (i.e. renal failure or EtOH abuse) that can also explain the patients hyponatremia.

Shunt fractions > 50% have no response to 100% FiO24. Acute causes of large shunt in the hospital include flash pulmonary edema, large aspiration event, pneumothorax and mucus plugging resulting in lobar collapse.

Causes of Secondary ITP

Additional Labs for Secondary ITP

Other laboratory studies to consider for evaluation and work-up of secondary causes of ITP3:

This section serves as a broad overview of different types of complications that occur after transplantation and their timing in relation to initial transplant. Draw in each row/category as you teach them. The added text in this section is highlighted by a green box and not in green text in order to showcase different marker colors.

Immunosuppression

Allogenicity can be thought of as a patient’s risk of rejection. It is the highest in the first month after transplant and decreases over time. This is important in understanding the type of immunosuppression used in induction (heavily immunosuppressing) and in maintenance.

For induction, high dose steroids are used in combination with anti-lymphocyte or anti-IL2 antibodies. These are very immunosuppressing and their effects can last for several months after their initial use (duration of effect depends in part on “depleting” vs. “nondepleting” antibodies)

mTOR inhibitors such as sirolimus and everolimus are also used in certain transplant patients.

Balancing Immunosuppresion

The first section of this talk is on balancing immunosuppresion. The new figures you will draw are added ingreen. Please look to the next figure for color coding this figure.

Too much immunosuppresion increases risk of infection and cancer, while too little results in rejection of the transplanted organ. Among the different transplant organs, lungs have the highest risk of rejection and livers hace the lowest risk. This risk is reflected in the number of maintenance immunosuppressant medications patients are on.

Board Set Up

Set up your board prior to the start of the lecture. Use different colored markers/chalk if possible. In general, medications and infectious/malignant complications appears as blue; rejection complications appear as red.

Additional spiculated pulmonary nodules are present in the left upper lobe (9 x 12 mm) and the right upper lobe (8 mm). These are suspicious for metastatic foci

Rheumatologic Labs

ESR 38 (H), CRP 124.5 (H)

ANA panel negative

ANCA positive 1:64

Anti-PR3 >80 (H)

Anti-MPO negative

Anti-GBM negative

Total complement 42

C3 – 84 (L)

C4 – 5 (L)

Multinucleated Giant Cell

Differential Diagnosis and Evaluation

The differential for hypoxia and dyspnea in the hospital can be differentiated into respiratory, cardiac, and other causes. Anything in the respiratory system (comprised of airways, alveoli, vessels) that is narrowed, blocked, or collapsed results in dyspnea and usually hypoxia. Walk through each level of your diagram (from upper airways down).

Cardiac and other causes may cause dyspnea with or without concurrent hypoxia. Walk through notable cardiac causes and then discuss the 3 “A’s” that comprise the “other” causes. Acidosis, for example, results in tachypnea without hypoxia.

In discussing work-up and evaluation, physical exam and response to oxygen is the first step. A CXR easily identifies any alveolar/parenchymal or pleural process. Alveolar processes in addition to bronchoconstruction and PE will result in a low PaO2.

The 5 Causes of Hypoxemia

Introduce part (1) as identifying and differentiating the 5 causes of hypoxemia, which can be separated by normal A-a gradient and elevated A-a gradient cause. While explaining the A-a gradient, draw the equation on the board.

Engage your learners in guessing the causes of normal A-a gradient hypoxemia. When, they identify decreased FiO2 as a cause, mark it with an “X” to denote that this is not relevant in the inpatient setting. Give examples of (or ask your learners to identify) each cause of hypoxemia as your learners identify them.

Next, engage your learners in identifying the remaining 3 causes of elevated A-a gradient hypoxemia. Differentiate shunt by its nonresponse to 100% FiO2. In fact, all other causes of hypoxemia except for a large shunt (> 50%) will correct with 100% FiO2. Mark out diffusion impairment as a notable cause of inaptient hypoxemia.

While giving examples of V/Q mismatch and shunt, you can illustrate them on the alveoli/vessel diagram. A PE and alveolar filling process are shown.

Teaching Instructions: Board Set Up

Prior to the start of the lecture, set up your board as detailed in the figure. Split the board in half. On one side, draw the flow sheet in (1) but leave the 5 causes of hypoxemia blank. On the other side, draw the diagram in (2).

You can teach either part 1 or 2 first. Teaching part 1 first builds a basic understanding of different pulmonary causes of hypoxemia that can help with differential building and understanding the utility of different laboratory tests in the evaluation of hypoxia in part 2. Teaching part 2 first helps lay a general ground work for how to think about dyspnea and hypoxia in the hospital before focusing in on pulmonary causes of hypoxia.

Labs and Imaging

CXR– differentiates and identifies any alveolar filling process, atelectasis or pleural processVenous blood gas– evaluates for a component of hypoventilation that could be contributing to hypoxia or metabolic acidosis driving respiratory rateArterial blood gas– in addition to information provided by a VBG, an ABG measures PaO2 (arterial partial pressure of oxygen) which confirms hypoxemia, can be used to calculate an A-a gradientEKG– assess for arrhythmias, ischemic changes, low voltages or electrical alternansEchocardiogram– while a formal TTE is not often possible in the immediate evaluation of new hypoxia, a bedside ultrasound can assess for presence of a pericardial effusion or signs of right ventricular overload (more skilled operators)Troponin– elevated in ACS or instances of demand ischemiaB-type naturietic peptide– elevated in heart failure exacerbationsBMP– identifies presence of acidosisCBC– identifies anemia

D-dimer testing is not included in the above list because it has limited utility in already hospitalized patients for evaluation of pulmonary embolism. If there is high suspicion of PE, a CTPE or V/Q scan should be considered for evaluation.

The FLORALI study (NEJM, 2015) was a multicenter study that randomized 313 patients with acute hypoxemic respiratory to receive HFNC, standard oxygen therapy (continuous NRB face mask) or NIPPV and evaluated intubation rates and mortality. The study found there was no statistically significant difference in intubation rates between the 3 groups at 28 days. However, there was a statistically significant difference in all cause mortality at 90 days and in ventilator free days at 28 days. Subgroup analysis did show that in patients with more severe hypoxemia (PaO2/FiO2 ratio < 200), there was a statistically significant difference in intubation rates at 28 days.

HFNC also potentially lower risk for reintubation. Hernandez, et al. in 2016 in JAMA randomized 527 patients to HFNC or conventional oxygen therapy (nasal cannula or NRB) after extubation. At 72 hours, reintubation rates were 4.9% in the HFNC group compared to 12.2% in the conventional group (p = 0.004). Subsequent studies9 looking at patients at higher risk for extubation failure have not demonstrated statistically significant difference.

Oxymizer

The graph on the left is a model of effective FiO2 for oxymizer compared to standard nasal cannula. Oxymizer consistently delivers ~ 8% higher FiO2 when compared to standard nasal cannula. The graph on the right is from the manufacter’s detail which shows that the fluidic oxymizer achieves similar FiO2‘s in the trachea as compared to high flow nasal cannula.

Streptoccal TSS skin rash

Image from Stevens, DL in Uptodate.

How does IVIg work?

IVIg can be considered as adjunctive therapy, but is not supported by robust clinical evidence. Theoretically, it provides anti-inflammatory and immunomodulatory effects by boosting antibody levels via passive immunity. It has been shown to improve mortality in retrospective, observational studies and only one small, randomized trial2,4.

How does adjunctive clindamycin therapy help?

Streptococcal species, in particular, Group A Streptococcus is very sensitive to beta-lactam inhibitors but monotherapy with penicillin has been associated with high mortality. The Eagle Effect is thought to be responsible in part for this high mortality rate1,2. Penicillins require actively replicating bacteria in order to inhibit bacterial wall synthesis. Large inoculums of bacteria reach a stationary growth phase and decrease expression of penicillin binding proteins, reducing the efficacy of penicillins.

Clindamycin adjunctive therapy improves outcomes when used in conjunction with beta-lactam therapy. Clindamycin reduces protein synthesis and decreases production of bacterial toxins. It may also decrease production of cytokines by our immune cells and modulate immune response.

ABG interpretation

He has an acute respiratory acidosis and evidence of hypercarbic respiratory (or ventilatory) failure. He is also hypoxemic with an elevated A-a gradient of >200.

Chest CT interpretation

Patchy basilar consolidation. Scattered bilateral small pulmonary nodules identified and may reflect an infectious process similar to basilar consolidation.

BAL cultures

Bacterial culture – stain negative, final culture negative

AFB stain and culture negative

Fungal stain and culture negative

Mycoplasma and Aspergillus PCR negative

PJP stain and PCR negative

Nocardia and Legionella cultures NGTD

Other

Pulmonary edema and pleural effusions are common in the early post operative setting because of the disruption of lymphatic drainage system during transplantation

Bronchial stenosis is the most common airway complication– Most commonly manifests in the first month post-transplant but sometimes manifests multiple years after transplant

Pulmonary emboli – higher incidence in lung transplant patients14
– VTE (including DVTs) occured in up to 49% of post lung transplant patients
– ~ 60% of VTEs occur within the first year after transplant (with 40% of these cases occuring in the first 3 months)

PTLD– Most common in the first year post-transplantation– Patients who are EBV seronegative have a higher risk of developing PTLD– Occurs in 2-8% of lung transplant patients– Cases that occur in the first year involve the grafted organ, but later cases can involve other organs (frequently the GI tract)6

Recurrent primary lung disease– Sarcoid has recurrence of 35% after lung transplant and has been reported between 2 weeks – 2 years post-transplant6

Pulmonary drug toxicity– Can occur with mTOR inhibitors (everolimus, sirolimus)– Most common within the first 6 months of starting therapy

Rejection

Infections

Bacterial

Make up the vast majority of post-transplant infections (40-60% of all infections)

Nosocomial organisms such as MRSA and Pseudomonas are most common in the first month after transplantation

Recurrent infections with gram negative bacteria (most commonly Pseudomonas) can occur years after transplant, particularly in patients with bronchiectasis or bronchiolitis obliterans

Fungal

Aspergillus– Most common fungal infection– High rates of post-transplant colonization– Invasive disease occurs in ~5% (with incidence ranging from 3-22%) of patients with most cases occuring in the first year3,4

Endemic mycoses – most commonly occur > 6 months out

Pneumocystic jirovecii pneumonia– Previously high incidence of infections but now is less commonly seen because of the use of prophylaxis– Most common 3-6 months post transplant4– May be sublinical in up to 50% of cases4

Viral

CMV– Mostly occurs 1-3 months after transplant, but increasing cases of delayed CMV infection with valganciclovir prophylaxis4,6– CMV negative recipients who receive CMV positive doonor lungs are at highest risk– Can involve any organ but common in transplanted organ